The mammalian endocrine system is critical to mammalian cell-cell communication. In the endocrine system, hormones are secreted by endocrine glands into the circulatory system and adsorbed onto specific receptors, usually located distal to the site of secretion. The endocrine system is used by mammals to orchestrate a variety of different physiological processes, including metabolism, growth and maturation, circadian cycles and the like.
An important member of the endocrine system is the hypothalamic-pituitary axis. In general, this member of the endocrine system has two components: 1) a magnocellular (large cell) system which releases the hormones oxytocin and vasopressin (arginine vasopressin, AVP) directly into the blood stream from axon terminals located in the posterior pituitary and 2) a parvocellular (small cell) system that secretes small peptides called releasing factors which enter fenestrated capillaries, descend through the hypophyseal portal veins, and then diffuse through additional fenestrated capillaries to individual cells of the anterior pituitary. Principal neuropeptides secreted by the hypothalamus include growth hormone releasing hormone (GHRH), growth hormone release-inhibiting hormone (somatostatin), prolactin release inhibitory factor (dopamine), gonadotropin-releasing hormone (GnRH), corticotropin-releasing hormone (CRH), and thyrotropin-releasing hormone (TRH). Hormones released by the pituitary in response to hypothalamus neuropeptide influence include growth hormone (GH), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH, corticotropin) and thyrotropin (thyroid stimulating hormone, TSH).
The magnocellular and parvocellular secretory regions of the hypothalamus receive strong inputs from a variety of regions including other segments of the hypothalamus, diverse areas of the brain stem, and from forebrain (telencephalic) structures. See FIG. 1. Prominent in the last group are projections from the limbic system including the central and medial divisions of the amygdala and the closely related bed nucleus of the stria terminals.
Abnormalities in endocrine or hormonal systems, e.g. hypo- or hypersecretion of one or more particular hormones, can have a profound affect on the ability of a mammal to function. For example, hypersecretion of pituitary hormones can result in a number of different diseased states, including: Cushing's syndrome (ACTH), acromegaly and gigantism (GH), and the like. Hyposecretion of pituitary hormones is also implicated in a number of diseased states, including dwarfism (GH), Sheehan's syndrome (panhypopituitarism), and the like.
Recently, age dependent dysfunction of hormonal systems has been postulated to be associated with the mammalian aging process. For example, GH blood levels in the elderly are lower than GH blood levels in younger populations, where lower GH blood levels have been theorized to be associated with symptoms of the aging process, such as decreases in lean body mass, muscle and bone.
Current methods of treating diseases associated with endocrine system dysfunction involving the hyposecretion of one or more particular hormones have centered on direct hormonal replacement, e.g. synthetic or recombinant growth hormone for GH deficient youths. While such approaches can be successful, hormone replacement therapy can be associated with a number of different disadvantages, such as risk of pathogen transmission, delivery, over compensation of replacement hormone, and the like.
As such, there continues to be an interest in the development of new methods of treating diseases characterized by endocrine system dysfunction. Of particular interest is the identification of small molecules which have a modulatory effect in the amount of endogenous hormone production, and methods of using such molecules in the regulation of hormonal circulatory levels.